Organic principles and research results
Although the disease mechanism of ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) is not yet fully understood, numerous pathophysiological abnormalities have been identified over the past 30 years that explain the multisystemic and severe symptoms of this disease.
Vascular dysfunction
One of the most commonly reproduced findings in ME/CFS is reduced blood flow in the brain. Costa et al. (1995) found significantly reduced blood flow in the brain stem in ME/CFS patients compared to healthy controls and people with depression. A large-scale study by van Campen et al. (2020) with over 400 ME/CFS patients showed that cerebral blood flow decreases on average by more than three times in the upright position compared to the supine position and that this decrease correlates with orthostatic intolerance.
Endothelial dysfunction is another common abnormality in ME/CFS. Newton et al. (2011) and Scherbakov et al. (2020) pointed out that ME/CFS is characterized by limited vasodilation, which leads to dysregulation of blood circulation and undersupply of organs and muscles. An in vitro study by Bertinat et al. (2022) showed that blood plasma from ME/CFS patients limits the production of nitric oxide (NO) by endothelial cells, which is important for vasodilation. In addition, Nunes et al. (2022) found overactivation of platelets and increased microclots in ME/CFS patients. Flaskamp et al. (2022) reported increased levels of autoantibodies that bind to endothelial cells.
As early as the 1980s, Simpson (1989) pointed out an altered shape of red blood cells in ME/CFS. Saha et al. (2019) showed that the red blood cells of ME/CFS sufferers deform 7 times less in the smallest channels and also flow more slowly than those of healthy controls. This limited deformability is important for a functioning microcirculation of the blood.
Disorders of energy metabolism
Due to the impaired blood circulation, it is assumed that the oxygen supply to the tissues may be reduced in ME/CFS. McCully and Natelson (1999) showed that after both exercise and artificially induced ischemia (blocked blood flow), the oxygen saturation in the leg muscles of ME/CFS sufferers increases more slowly than in healthy controls. Tanaka et al. (2002) and Neary et al. (2008) reported reduced oxygen saturation in the brain in a standing position and during or after maximal exercise in ME/CFS patients. Joseph et al. (2021) found a limited systemic oxygen supply in ME/CFS in a large study using an invasive cardiopulmonary exercise test.
Oxygen is necessary for aerobic energy production. When there is a lack of oxygen, body cells switch to the less efficient anaerobic energy production, which produces lactate. Numerous studies have shown increased lactate levels in the cerebrospinal fluid (cerebrospinal fluid) in ME/CFS patients. For example, Matthew et al. (2008) found ventricular lactate levels in ME/CFS sufferers that were 3.5 times higher than in healthy controls. Lien et al. (2019) showed that ME/CFS sufferers had higher lactate levels during a cardiopulmonary exercise test (CPET) for the same performance, which became even more evident in a repeated CPET after 24 hours. In a meta-analysis, Franklin and Graham (2022) confirmed a sharp drop in the anaerobic threshold with repeated CPET, which objectifies the cardinal symptom of ME/CFS, post-exertional malaise.
For the body's most important energy source, glucose, Tirelli et al. (1998) and Siessmeier et al. (2003) used positron emission tomography to show a significantly lower uptake of glucose in the brain in some ME/CFS sufferers.
Disturbed adrenergic and acetylcholinergic signaling
A large part of the body's functions are unconsciously controlled by the autonomic nervous system (ANS). Studies by Spence et al. (2004) and Yamamoto et al. (2012) showed that signal transmission via acetylcholine receptors is disrupted in ME/CFS patients. Kavelaars et al. (2000) and Hartwig et al. (2020) found that ß2-adrenoreceptors respond less strongly to signal transmission in ME/CFS. In addition to the ANS, these receptors are also found on blood and immune cells and influence the cytokine production of monocytes.
Autoantibodies against G-protein-coupled receptors
Several studies measure increased titers of autoantibodies (AAB) against various G protein-coupled receptors (GPCR) in some ME/CFS sufferers, which are involved in blood flow regulation, among other things. Freitag et al. (2021) showed a clear connection between the level of autoantibodies and the severity of ME/CFS symptoms. However, the ELISA technique for determining GPCR AAB titers has its limitations, as it only measures the level of antibodies, not their functional activity.
Replications in Long-COVID
Many of the pathophysiological findings in ME/CFS have also been demonstrated in long-COVID patients. These include reduced cerebral blood flow, endothelial dysfunction, GPCR autoantibodies, and impaired energy metabolism in the brain.
Conclusion
The scientific literature shows numerous physiological abnormalities in ME/CFS, which together provide a clear picture of the disease. These include disturbances in blood flow regulation, energy metabolism and the autonomic nervous system, as well as evidence of autoantibodies. In order to deepen the findings and develop diagnostic biomarkers, further research with large samples and state-of-the-art methods is necessary.
An important concern of future research should be the financing and standardization of diagnostic procedures in order to create uniform and comparable cohorts and to place the results in the context of the literature already published. Findings from related clinical pictures such as POTS or Long COVID can also provide valuable information.